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De Novo Purine Metabolism is a Metabolic Vulnerability of Cancers with Low p16 Expression
Tangudu, Naveen Kumar Buj, Raquel Wang, Hui Wang, Jiefei Cole, Aidan R. Uboveja, Apoorva Fang, Richard Amalric, Amandine Yang, Baixue Chatoff, Adam
Tangudu, Naveen Kumar
Buj, Raquel
Wang, Hui
Wang, Jiefei
Cole, Aidan R.
Uboveja, Apoorva
Fang, Richard
Amalric, Amandine
Yang, Baixue
Chatoff, Adam
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Journal article
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2024-05-02
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Cardiovascular Sciences
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https://doi.org/10.1158/2767-9764.crc-23-0450
Abstract
p16 is a tumor suppressor encoded by the CDKN2A gene whose expression is lost in approximately 50% of all human cancers. In its canonical role, p16 inhibits the G1–S-phase cell cycle progression through suppression of cyclin-dependent kinases. Interestingly, p16 also has roles in metabolic reprogramming, and we previously published that loss of p16 promotes nucleotide synthesis via the pentose phosphate pathway. However, the broader impact of p16/CDKN2A loss on other nucleotide metabolic pathways and potential therapeutic targets remains unexplored. Using CRISPR knockout libraries in isogenic human and mouse melanoma cell lines, we determined several nucleotide metabolism genes essential for the survival of cells with loss of p16/CDKN2A. Consistently, many of these genes are upregulated in melanoma cells with p16 knockdown or endogenously low CDKN2A expression. We determined that cells with low p16/CDKN2A expression are sensitive to multiple inhibitors of de novo purine synthesis, including antifolates. Finally, tumors with p16 knockdown were more sensitive to the antifolate methotrexate in vivo than control tumors. Together, our data provide evidence to reevaluate the utility of these drugs in patients with p16/CDKN2Alow tumors as loss of p16/CDKN2A may provide a therapeutic window for these agents.
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Naveen Kumar Tangudu, Raquel Buj, Hui Wang, Jiefei Wang, Aidan R. Cole, Apoorva Uboveja, Richard Fang, Amandine Amalric, Baixue Yang, Adam Chatoff, Claudia V. Crispim, Peter Sajjakulnukit, Maureen A. Lyons, Kristine Cooper, Nadine Hempel, Costas A. Lyssiotis, Uma R. Chandran, Nathaniel W. Snyder, Katherine M. Aird; De Novo Purine Metabolism is a Metabolic Vulnerability of Cancers with Low p16 Expression. Cancer Research Communications 1 May 2024; 4 (5): 1174–1188. https://doi.org/10.1158/2767-9764.CRC-23-0450
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American Association for Cancer Research (AACR)
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Cancer Research Communications, Vol. 4, Iss. 5
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